Combing Through the Tangles of Alzheimer’s

Researchers are homing in on the tau protein as a likely culprit in the development of Alzheimer’s disease.

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If the brain operates like a superhighway, Alzheimer’s disease aims to tangle it with inefficient routes and traffic jams, ultimately creating a shutdown. Researchers are still uncovering how this happens.

Alzheimer's is the only cause of death among the top 10 in America that cannot be prevented, cured or even slowed. It has no current cure and no treatment can stop its progression, but available treatments for symptoms can temporarily slow the worsening of dementia symptoms and help improve quality of life for those with Alzheimer’s and their caregivers.
It’s estimated that in 2015, nearly 47 million people live with dementia, a set of symptoms that includes the deterioration of thinking and memory not associated with the normal signs of aging. Alzheimer’s disease – the most common cause of dementia – may contribute to 60 to 70 percent of all dementia cases.

Buildup of plaque and tangles

It’s thought that two proteins play a critical role in the development of Alzheimer’s disease – the buildup of amyloid-β into structures called plaques and tau into structures known as neurofibrillary tangles.

For years, the focus of Alzheimer’s researchers like David Holtzman, M.D., chairman, Department of Neurology, Washington University, St. Louis, Missouri, was into the role of amyloid-β. In healthy brains, amyloid-β is cleared out of the brain on a regular basis, preventing its accumulation. Researchers focused on this abnormal amyloid-β buildup in Alzheimer’s disease as possibly disrupting the processes that cells need to survive.
While many scientists also believed that tau accumulation also played a role in brain dysfunction, more recently researchers, including Dr. Holtzman, focused on not only whether tau contributes to causing Alzheimer’s disease, but also whether it may be a potential target for treating it.
Tau is a normal protein that lives in the brain and, like the ties on railroad tracks, its purpose is to help nerve cells transport the materials they need to function. In Alzheimer’s, tau is thought to fall off the railroad tracks – and form neurofibrillary tangles.

“What happens in Alzheimer’s is that this floppy linear protein, tau, that normally organizes into a highly efficient cable starts to misfold on itself, piles up and destroys neurons, spreading from region to region until the entire cortex of the brain is invaded,” says Joel Braunstein, M.D., MBA, president, co-founder and CEO of C2N Diagnostics.
The abnormal accumulation of amyloid-β and tau is thought to somehow play a critical role in blocking communication among nerve cells and disrupting processes that cells need to survive.
“Tau starts building up in regions of the brain associated with memory and spatial navigation. Once those areas are affected, the first clinical symptoms of the disease, forgetfulness and often disorientation, begin to show,” says Jim Summers, Ph.D., vice president of neuroscience discovery at AbbVie.
Now researchers are beginning to understand the connection of amyloid- β and tau to Alzheimer’s. “The research community is beginning to uncover how tau misfolds, spreads and forms tangles and its relationship to amyloid-β. Unraveling these mechanisms is pointing us to new approaches to treat the disease,” he says.

What's next?

Researchers, including AbbVie, in partnership with Dr. Holtzman and C2N, are identifying ways to block the tangling of tau and how it spreads through the brain in the early stages of the disease.
“Scientific discovery, particularly with the complexities of Alzheimer’s disease, doesn’t happen in isolation,” Summers says. “Partnerships are key to us sharing knowledge and expertise, and it means we have the potential to help patients and their families at a faster pace than working alone.”

Identifying those at risk

Even with advances in the understanding of Alzheimer’s, challenges remain in identifying people at increased risk of developing it. Dr. Holtzman, together with colleague Randall Bateman, M.D., professor of neurology at Washington University, developed a platform offered by C2N that aims to identify the biomarkers for Alzheimer’s disease through a simple test. The test, called Stable Isotope Labeling Kinetics (SILK™), could provide doctors the potential to identify those more prone to the disease, screen earlier and manage them at an earlier age.
“Patients who are showing early signs of the disease or more importantly, before outward symptoms develop, could benefit from this type of screening so we can see what’s happening in the brain. If such a test works, we could then go on to get a more definite test for amyloid deposition with a brain scan,” Holtzman says.
AbbVie is part of a consortium of companies and academics institutions partnering with C2N on this technology.

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